Inherited genetic risk is a major component of Type I diabetes (T1D). Major international research efforts have identified a large number of T1D susceptibility genes through genome wide association studies (GWAS). Despite these advances, in nearly all cases GWAS "hits" have not yielded insight into protein coding alterations but rather are presumed to reflect regulatory SNPs or haplotypes that have refractory to detection. To address the intractable problem of missing hereditability in the post-GWAS era we have assembled a uniquely qualified interdisciplinary team, both to extract maximum information from GWAS and to pursue "post-GWAS" pathogenic epigenetic events. Our innovative approach to this question focuses on both aberrations of T cells and end- organ vulnerability. We have assembled both T1D immunologists and beta cell biologists to team with molecular geneticists/epigeneticists and an experienced bioinformatician in a systems approach to identify therapeutically targetable genome wide epigenetic events in the relevant cytotoxic T cells and their targets. Using mouse models and human subjects recruited through the diabetes clinical centers at Columbia/Yale, T1D specific epigenetic hits will be identified with clinical predictive utility and mechanistic importance. Therapeutic opportunities for reversal will be pursued using novel antisense approaches. Our approach has already identified key epigenetically regulated immunological targets modulating tolerance (CD3, PD-1), and has developed pioneering T1D monitoring tools to define the prediabetic window of insulitis (hypomethylated insulin). Novel epigenetic-based therapeutic approaches are proposed and tested that represent an innovative strategy for inducing endogenous anti-inflammatory isoforms, including endogenous soluble cytokine receptors and ligand independent inhibitory costimulatory molecules. In addition, we will use allele-specific mapping of DNA methylation and gene expression to help extract maximum information from GWAS and re-sequencing data for T1D susceptibility loci. In sum this project will identify genetic and epigenetic events responsible for T1D susceptibility and disease progression, and pursue therapeutic approaches directed at known and novel genetic and epigenetic targets. PUBLIC HEALTH RELEVANCE: Heritable risk in Type 1 diabetes has been extensively studied but remains poorly defined. We will use epigenetic tools to bolster the genetic data, and to find genetic variants that are responsible for aberrant activity of killer T cells and the vulnerability of the end organ islet cells. Treatment opportunities to correct genetically and epigenetically dysregulated genes will be pursued with antisense approaches.